14-72981895-C-A

Position:

• chr14-72981895-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021260.4(ZFYVE1):​c.1204G>T​(p.Ala402Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFYVE1 NM_021260.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

ZFYVE1 (HGNC:13180): (zinc finger FYVE-type containing 1) The FYVE domain mediates the recruitment of proteins involved in membrane trafficking and cell signaling to phosphatidylinositol 3-phosphate-containing membranes. This protein contains two zinc-binding FYVE domains in tandem and is reported to localize to the Golgi apparatus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE1	NM_021260.4	c.1204G>T	p.Ala402Ser	missense_variant, splice_region_variant	5/12	ENST00000556143.6	NP_067083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE1	ENST00000556143.6	c.1204G>T	p.Ala402Ser	missense_variant, splice_region_variant	5/12	1	NM_021260.4	ENSP00000450742.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.1204G>T (p.A402S) alteration is located in exon 5 (coding exon 4) of the ZFYVE1 gene. This alteration results from a G to T substitution at nucleotide position 1204, causing the alanine (A) at amino acid position 402 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.5	.;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.98	D;.;D
Vest4		0.67
MutPred		0.26		Gain of disorder (P = 0.0172);Gain of disorder (P = 0.0172);Gain of disorder (P = 0.0172);
MVP		0.38
MPC		0.46
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.12
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-73448603;